The long term objectives of this research program are to utilize newly found immunological mutants of the mouse to investigate the etiology of immunodeficiency and autoimmune diseases. This research proposal focuses on phenotypic abnormalities caused by deleterious alleles at the motheaten locus. Homozygosity for the "motheaten" (me) and "viable motheaten" (mev) mutations results in the most severe genetically determined immunologic dysfunction known in experimental animals. It is hypothesized that these mutations cause microenvironmental defects demonstrable at the level of hematopoietic progenitors in the fetal liver and bone marrow. The main objectives of the current program are to assess the roles of hematopoietic progenitor cell abnormalities and microenvironmental defects in the development of immunopathologic changes in me/me and mev/mev mice. The specific aims include: determination of the cellular basis for defective thymic repopulation following intravenous transfer of bone marrow cells from mev/mev mice into irradiated normal recipients; assessment of dendritic accessory cell abnormalities in me/me and mev/mev mice; determination of the role of hematopoietic progenitor abnormalities in development of immunopathologic changes in these mice; and evaluation of genetic interactions between deleterious alleles at the motheaten locus and the "severe combined immunodeficiency" (scid) locus. These studies will contribute to an understanding of complex immunologic diseases and increase our understanding of the immune system in normal and pathologic states.